LINOLEIC ACID UNLEASHES THE ANTI-TUMOR POTENTIAL OF CD8 T CELLS BY PROMOTING METABOLIC REPROGRAMMING
type: CreativeWork
description: T cell therapy (ACT) has achieved unprecedented clinical results in the treatment of cancer, but scarce intra-tumor infiltration, persistence and function of adoptively transferred T cells limit its efficacy, especially in solid tumors. Metabolic constraints imposed by the tumor microenvironment (TME) greatly influence the success of immune-based therapies. A common metabolic alteration in the TME is lipid accumulation, a feature often associated with defective anti-tumor responses. However, whether all lipids are detrimental to T cell functions and how they regulate different fate decisions remains poorly understood. Here, we identified Linoleic Acid (LA) as a major positive regulator of CTL activity. LA endows CTL with improved metabolic fitness and redirects them away from exhaustion and towards a memory-like phenotype with superior effector functions. Mechanistically, LA treatment fosters the formation of ER-mitochondria contacts (MERC) and mitochondrial-associated-membranes (MAMs), which in turn promotes calcium (Ca2+) signaling, mitochondrial energetics, and CTL effector functions. As a result, LA-instructed CD8+ T cells mediate superior control towards different tumor types both in vitro and in vivo following ACT on mouse models, overcoming the hustle of a highly immunosuppressive TME. Our results pave the way for a new generation of adoptive T cell-based therapies, where LA can be used during ex vivo CAR- and TCR- T cell manufacturing as a novel approach to achieve metabolic reprogramming and long-term functionality, broadening the therapeutic efficacy of ACT to a wide range of malignancies.
abstract: T cell therapy (ACT) has achieved unprecedented clinical results in the treatment of cancer, but scarce intra-tumor infiltration, persistence and function of adoptively transferred T cells limit its efficacy, especially in solid tumors. Metabolic constraints imposed by the tumor microenvironment (TME) greatly influence the success of immune-based therapies. A common metabolic alteration in the TME is lipid accumulation, a feature often associated with defective anti-tumor responses. However, whether all lipids are detrimental to T cell functions and how they regulate different fate decisions remains poorly understood. Here, we identified Linoleic Acid (LA) as a major positive regulator of CTL activity. LA endows CTL with improved metabolic fitness and redirects them away from exhaustion and towards a memory-like phenotype with superior effector functions. Mechanistically, LA treatment fosters the formation of ER-mitochondria contacts (MERC) and mitochondrial-associated-membranes (MAMs), which in turn promotes calcium (Ca2+) signaling, mitochondrial energetics, and CTL effector functions. As a result, LA-instructed CD8+ T cells mediate superior control towards different tumor types both in vitro and in vivo following ACT on mouse models, overcoming the hustle of a highly immunosuppressive TME. Our results pave the way for a new generation of adoptive T cell-based therapies, where LA can be used during ex vivo CAR- and TCR- T cell manufacturing as a novel approach to achieve metabolic reprogramming and long-term functionality, broadening the therapeutic efficacy of ACT to a wide range of malignancies.
author: NAVA LAUSON, CARINA B.
language: eng
keywords: linoleic acid, T cell, CAR-T, adoptive cell therapy, metabolism, metabolic reprogramming, Settore MED/04 - Patologia Generale
date published: 2023-04-13
date modified: 2026-07-27T20:18:56Z
provider: Università degli Studi di Milano
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: Università degli Studi di Milano

PropertyValue
property ID: Handle
value: https://hdl.handle.net/2434/958937

PropertyValue
property ID: DOI
value: 10.13130/nava-lauson-carina-b-_phd2023-04-13